Clinical2020
In a 220-subject phase 2 trial, NSI-189 40 mg/day did not show statistically significant separation from placebo on the primary endpoint overall, but was generally well tolerated.
Neurogenesis
anecdotal
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NSI-189
Overview
NSI-189 is a small molecule neurogenic compound (technically a benzylpiperazine-aminopyridine, not a peptide) developed to stimulate neurogenesis in the hippocampus. The compound was discovered through screening for molecules that promote hippocampal neural stem cell proliferation. Research demonstrates NSI-189 increases hippocampal volume, enhances synaptic plasticity, and improves cognitive and emotional processing in preclinical models. Phase 2 clinical trials evaluated NSI-189 for major depressive disorder, showing improvements in cognitive function and some measures of depression, though primary efficacy endpoints produced mixed results. The mechanism of action involves stimulation of hippocampal neurogenesis, potentially addressing the neurodegenerative aspects of depression and cognitive decline. Studies indicate benefits for spatial and verbal memory, processing speed, and executive function. NSI-189 represents a novel mechanism-based approach to neuropsychiatric conditions that targets brain structure and plasticity rather than neurotransmitter modulation alone. Research continues into applications for depression, cognitive impairment, and neurodegenerative diseases.
Last reviewed: 2026-08-18
Identity & Aliases
Also known as
NSI-189 phosphate6-(4-benzylpiperazin-1-yl)pyridin-3-ylmethanamineNeuralstem NSI-189
Status: Research compound - Neurogenic compound
CAS1270138-40-3
PubChem25182950Full composition (formula, molecular weight, sequence) in Quick Facts →
Research Areas
Major depressive disorderHippocampal neurogenesisCognitive dysfunction
Available Evidence
Human
A 220-patient phase 2 RCT in major depressive disorder (Molecular Psychiatry) found NSI-189 40 mg/day was generally well tolerated but did not separate from placebo on the primary endpoint overall; a post-hoc analysis reported significant benefit in moderately depressed patients. The sponsor reported that a subsequent phase 2b trial missed its primary endpoint, and no phase 3 trial has been registered.
Animal
Rodent studies show NSI-189 stimulates hippocampal neurogenesis and exerts antidepressant-like effects in behavioral models.
In Vitro
Cell-culture studies report NSI-189 increases proliferation of human hippocampal progenitor cells.
Uncertain
Claims that NSI-189 'regrows the brain' or enhances cognition in healthy people are unproven; its neurogenesis-based antidepressant mechanism has not been validated in humans.
Key Studies & Findings
Clinical2020
Post-hoc analysis of the phase 2 study reported that NSI-189 selectively benefited moderately depressed patients.
Benefits & Effects
Side Effects & Safety
Mild side effect
MildCommon (most frequent) Reversible
Onset: During treatment
Management: Standard analgesics
Mild side effect
MildCommon Reversible
Onset: During treatment
Management: Dose reduction if severe
Dose-dependent
Limitations & Open Questions
NSI-189 is a small molecule, not a peptide, and development appears stalled: the phase 2b study missed its primary endpoint and no phase 3 was registered. The neurogenesis hypothesis remains unconfirmed in humans, and cognitive-enhancement use has no clinical support.
Pharmacology
Orally administered small-molecule phosphate salt. Proposed mechanism: stimulation of hippocampal neurogenesis via an incompletely characterized molecular target; human pharmacokinetics are not well described in the published literature.
Reported Research Dosing
Reported values from research literature and community protocols. Educational reference only — not a dosing recommendation or medical advice.
40-80mg daily
Route: Oral
Half-life: 15-20 hours
Frequently Asked Questions
Is NSI-189 a peptide?
No. It is a small-molecule compound (a benzylpiperazine-aminopyridine) developed by Neuralstem to stimulate hippocampal neurogenesis.
Did NSI-189 work in clinical trials?
The published phase 2 trial did not meet its primary endpoint overall (post-hoc analysis suggested benefit in moderate depression), and the later phase 2b was reported as missing its endpoint; no phase 3 followed.
Is NSI-189 available as a treatment?
No. It is not approved by any regulator and is sold only as a research chemical.
Research Citations
2
The neurogenic compound, NSI-189 phosphate: a novel multi-domain treatment capable of pro-cognitive and antidepressant effects.
McIntyre RS, Johe K, Rong C, Lee Y (2017)
3
NSI-189 phosphate, a novel neurogenic compound, selectively benefits moderately depressed patients: A post-hoc analysis of a phase 2 study of major depressive disorder.
Johe KK, Kay G, Kumar S, Burdick KE, McIntyre RS, Papakostas GI, Fava M (2020)
4
NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.
Tajiri N, Quach DM, Kaneko Y, Wu S, Lee D, Lam T, Hayama KL, Hazel TG, Johe K, Wu MC, Borlongan CV (2017)
5
Enhancement of Mitochondrial Function by the Neurogenic Molecule NSI-189 Accompanies Reversal of Peripheral Neuropathy and Memory Impairment in a Rat Model of Type 2 Diabetes.
Jolivalt CG, Aghanoori MR, Navarro-Diaz MC, Han MM, Sanchez G, Guernsey L, Quach D, Johe K, Fernyhough P, Calcutt NA (2022)
+ 9 more citations
Related Resources
Quick Facts
Formula
C22H30N2O2
Molecular Weight
366.46
Mechanism
Neurogenesis stimulator for hippocampal growth
Safety Information
Research compound with Phase 2 trials for depression. Limited safety data.
Citations
142.The neurogenic compound, NSI-189 phosphate: a novel multi-domain treatment capable of pro-cognitive and antidepressant effects.
McIntyre RS, Johe K, Rong C, Lee Y (2017)
3.NSI-189 phosphate, a novel neurogenic compound, selectively benefits moderately depressed patients: A post-hoc analysis of a phase 2 study of major depressive disorder.
Johe KK, Kay G, Kumar S, Burdick KE, McIntyre RS, Papakostas GI, Fava M (2020)
4.NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.
Tajiri N, Quach DM, Kaneko Y, Wu S, Lee D, Lam T, Hayama KL, Hazel TG, Johe K, Wu MC, Borlongan CV (2017)
5.Enhancement of Mitochondrial Function by the Neurogenic Molecule NSI-189 Accompanies Reversal of Peripheral Neuropathy and Memory Impairment in a Rat Model of Type 2 Diabetes.
Jolivalt CG, Aghanoori MR, Navarro-Diaz MC, Han MM, Sanchez G, Guernsey L, Quach D, Johe K, Fernyhough P, Calcutt NA (2022)
+ 9 more citations